rs121918296

Variant names:

• chr11-64207412-G-A
• rs121918296
• NM_031471.6:c.48G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_031471.6(FERMT3):​c.48G>A​(p.Trp16*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FERMT3 NM_031471.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.29
• Publications: 6 publications found

Genes affected

FERMT3 (HGNC:23151): (FERM domain containing kindlin 3) Kindlins are a small family of proteins that mediate protein-protein interactions involved in integrin activation and thereby have a role in cell adhesion, migration, differentiation, and proliferation. The protein encoded by this gene has a key role in the regulation of hemostasis and thrombosis. This protein may also help maintain the membrane skeleton of erythrocytes. Mutations in this gene cause the autosomal recessive leukocyte adhesion deficiency syndrome-III (LAD-III). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2010]

FERMT3 Gene-Disease associations (from GenCC):

• leukocyte adhesion deficiency 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64207412-G-A is Pathogenic according to our data. Variant chr11-64207412-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2709.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031471.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT3	NM_031471.6	MANE Select	c.48G>A	p.Trp16*	stop_gained	Exon 2 of 15	NP_113659.3
	FERMT3	NM_001382362.1		c.48G>A	p.Trp16*	stop_gained	Exon 2 of 15	NP_001369291.1	Q86UX7-1
	FERMT3	NM_178443.3		c.48G>A	p.Trp16*	stop_gained	Exon 2 of 15	NP_848537.1	Q86UX7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT3	ENST00000345728.10	TSL:1 MANE Select	c.48G>A	p.Trp16*	stop_gained	Exon 2 of 15	ENSP00000339950.5	Q86UX7-2
	FERMT3	ENST00000279227.10	TSL:1	c.48G>A	p.Trp16*	stop_gained	Exon 2 of 15	ENSP00000279227.5	Q86UX7-1
	FERMT3	ENST00000698865.1		c.48G>A	p.Trp16*	stop_gained	Exon 2 of 15	ENSP00000513992.1	A0A8V8TP41

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Leukocyte adhesion deficiency (1)
1	-	-	Leukocyte adhesion deficiency 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.3
Vest4		0.28
GERP RS		4.5
PromoterAI		0.0094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121918296; hg19: chr11-63974884;